Background and Relevance. Atherosclerotic stenosis of the major intracranial arteries causes 40,000 strokes per year in the USA, costing the country at least 600,000,000 dollars annually. There have been no prospective trials evaluating optimal medical therapy for this disease. The main objective of this clinical trial is to compare warfarin (INR 2-3) with aspirin (1300 mg/day) for preventing stroke (ischemic and hemorrhagic) and vascular death in patients with symptomatic stenosis of a major intracranial artery. Study Design. Prospective, randomized, double-blind, multi-center trial. The sample size required will be 403 patients per group (based on stroke and vascular death rates of 33 percent/3 years in the aspirin group vs 22 percent/3 years in the warfarin group, an alpha of 0.05, beta of 0.80, a 24 percent withdrawal of therapy rate, and a 1 percent drop out rate). Conduct of Trial. Patients with transient ischemic attack (TIA) or stroke caused by angiographically proven stenosis (greater than or equal to 50 percent) of a major intracranial artery will be randomized to warfarin or aspirin. The dose of warfarin will be adjusted to maintain the INR between 2-3 based on monthly blood tests. Patients will be contacted monthly by phone and examined every four months (mean follow-up of 3 years) to determine whether any endpoints have occurred. The primary analysis will compare the rates of stroke (ischemic and hemorrhagic) and vascular death in the two treatment groups. Secondary analyses will compare the two treatment groups with respect to rates of i) all vascular deaths and disabling stroke, ii) all stroke (ischemic and hemorrhagic), iii) fatal and nonfatal ischemic stroke, iv) all ischemic stroke, myocardial infarction and vascular death, v) all major systemic and any intracranial hemorrhage, vi) all ischemic stroke in the territory of the stenotic intracranial artery. Conclusion. This study will 1) define optimal medical therapy for patients with symptomatic intracranial arterial stenosis, and 2) identify patients whose rate of ischemic stroke in the territory of the stenotic intracranial artery on best medical therapy is sufficiently high (i.e., greater than or equal to 6 percent per year) to justify a subsequent trial comparing intracranial angioplasty with best medical therapy in these patients.